Nicotine and learning interact to alter transcription factor activity at the c-jun N-terminal kinase 1 gene promoter in the hippocampus

Abstract

Approximately 1 in 5 Americans smoke despite the widely known negative health consequences of the habit. One factor that contributes to the high rates of nicotine addiction and its continued use is the ability of the drug to alter long-term memory. Learning in the presence of nicotine results in changes to the cellular and molecular processes that support the formation and storage of long-term memories. The consolidation of long-term memory requires a number of mechanisms, such as gene transcription. Previous work has found that learning a contextual fear conditioning task in the presence of nicotine results in the upregulation of the c-jun N-terminal kinase (JNK1) gene in the hippocampus and that JNK protein activation is necessary for the nicotine induced enhancement of contextual conditioning. The present study examines the transcription factors involved in the transcriptional regulation of jnk1 in the hippocampi of mice following learning in the presence of nicotine. The hypothesis that cAMP response element binding protein (CREB) regulates jnk1 transcription was examined. Further, a protein/DNA transcription factor array was used as an unbiased examination of changes in transcription factor activity following learning in the presence of nicotine. Using chromatin immunoprecipitation (ChIP), transcription factors identified from the array and CREB were examined for changes in their binding to the jnk1 promoter following fear conditioning in the presence of nicotine. An increase in the binding of phosphorylated CREB was found in the jnk1 promoter of mice trained in the presence of nicotine. This implicates CREB activation in the increase of jnk1 transcription following learning in the presence of nicotine. Additionally, data from the transcription factor array suggest other factors such as PARP, TR, USF-1 and E2F-1 as potentially playing a role in the cognitive effects of nicotine. These findings are discussed with respect to how they inform our understanding of the signaling cascades and genetics involved in the memory enhancing effects of this addictive drug.